1,5 anhydroglucitol and the monitoring of postprandial glucose control steven d wittlin m.d. u of...

1,5 Anhydroglucitol and 1,5 Anhydroglucitol and the Monitoring of the Monitoring of

Postprandial Glucose Postprandial Glucose ControlControl

Steven D Wittlin M.D.Steven D Wittlin M.D.

U of Rochester School of U of Rochester School of Medicine and DentistryMedicine and Dentistry

Importance of Post-Importance of Post-Prandial HyperglycemiaPrandial Hyperglycemia

Duration of daily metabolic Duration of daily metabolic conditionsconditions

Breakfast Lunch Dinner 0:00 am 4:00 am Breakfast

Postprandial Postabsorptive Fasting

Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11

0

2

4

6

8

10

12

14

16

0 5 10 15 20 25

2 hr af ter OGTT plasma glucose (mmol/ l)

2 h

r af

ter

SM

M p

lasm

a gl

ucos

e (m

mol

/l)

0

2

4

6

8

10

12

14

16

0 5 10 15 20 25

2 hr af ter OGTT plasma glucose (mmol/ l)

2 h

r af

ter

SM

M p

lasm

a gl

ucos

e (m

mol

/l)

Correlation between plasma glucose levels Correlation between plasma glucose levels after OGTT and standard mixed mealafter OGTT and standard mixed meal

Wolever TMS et al. Diabetes Care 1998;21:336–40

r=0.97r=0.97

Relationship between HbA1C, FPG and 2 h. PPGRelationship between HbA1C, FPG and 2 h. PPG

Van Haeften T et al Metabolism 2000Van Haeften T et al Metabolism 2000

Woerle HJ et al Arch Intern Med. 2004;164:1627-1632.

Relative Changes in FPG and 2-h PG Relative Changes in FPG and 2-h PG

as HbAas HbA1c1c Increases Increases

4 5 6 7

70

160

250

Pla

sma

Glu

cose

(mg

/dL

)

= HbA1c versus 2hppg= HbA1c versus FPG

r = 0.55y = 47.1 x -109

r = 0.48y = 12.0 x +30

HbA1c (%)

Relationship between FPG and 1Relationship between FPG and 1stst-Phase -Phase

Insulin ReleaseInsulin Release ( van Haeften T et al Metabolism 2000 )( van Haeften T et al Metabolism 2000 )

Relationship Between Diabetes Status Relationship Between Diabetes Status

and 1and 1stst Phase Insulin Release Phase Insulin Release ( van Haeften T et ( van Haeften T et

al .Metabolism 2000 )al .Metabolism 2000 )

As Patients Get Closer to A1C Goal, As Patients Get Closer to A1C Goal, the Need to Successfully the Need to Successfully

Manage PPG Significantly IncreasesManage PPG Significantly IncreasesIncreasing Contribution of PPG as A1C Improves

30%40% 45% 50%

70%

60% 55% 50%30%

70%

0%

20%

40%

60%

80%

100%

< 10.2 10.2 to 9.3 9.2 to 8.5 8.4 to 7.3 < 7.3

A1C Range (%)

%

Co

ntr

ibu

tio

n

FPGPPG

Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and postprandial plasnma glucose increments to the overall diurnal hyper glycemia of Type 2 diabetic patients: variations with increasing levels of HBA(1c).Diabetes Care. 2003;26:881-885.

Post-load Hyperglycemia and The Post-load Hyperglycemia and The Metabolic SyndromeMetabolic Syndrome

–0.13

–0.03

0.18

0.07

0.01

0.15

0.01

0.21*

Fasting plasmaglucose

0.20*

0.25‡

0.25‡

0.27‡

0.23*

0.21*

0.24*

0.25*

2-hr plasmaglucose

C-reactive protein

Cellular fibronectin

Tissue plasminogen activator (TPA)

Free fatty acids

Triglycerides

Waist: hip ratio

Body mass index (BMI)

Age

Yudkin JS. Lancet 2002;359:166–7 *p<0.05; ‡ p<0.01

Controlling Postprandial GlucoseControlling Postprandial Glucose Prospective trial of fasting vs pc control in 164 pts w/ Type Prospective trial of fasting vs pc control in 164 pts w/ Type

2 DM2 DM Forced titration to target first FBS < 100 and then, 90 min Forced titration to target first FBS < 100 and then, 90 min

pc < 140 if not achieved previouslypc < 140 if not achieved previously Results:Results:

HbA1C fell from 8.7 % to 6.5%HbA1C fell from 8.7 % to 6.5% Only 64% of patients achieving FPG < 100 only reached HbA1C Only 64% of patients achieving FPG < 100 only reached HbA1C

< 7%< 7% 94% of patients w/ pc < 140 reached HbA1C < 7%94% of patients w/ pc < 140 reached HbA1C < 7% Decreased pc BG accounted nearly twice as much as FBS for Decreased pc BG accounted nearly twice as much as FBS for

fall in HbA1Cfall in HbA1C If HbA1C < 6.2% , pc accounted for ~ 90%If HbA1C < 6.2% , pc accounted for ~ 90% If HbA1C > 8.9%, pc accounted for ~ 40%If HbA1C > 8.9%, pc accounted for ~ 40%

Woerle HJ et al Diabetes Research and Clinical Practice 2007

Contribution of Postprandial BG to HbA1CContribution of Postprandial BG to HbA1C

0

20

40

60

80

100

4.7-6.2 6.2-6.8 6.8-7.3 7.3-7.8 7.8-8.9 8.9-15.0HbA1c sixtiles(%)

Con

trib

utio

n (%

)

*=p<0.05vs HbA1c <6.2 %

*

*

*

**

Woerle HJ et al Diabetes Res Clin Pract. 2007 Jan 19

Glycemic Excursions Predict Glycemic Excursions Predict Oxidative StressOxidative Stress

Monnier L et al JAMA. 2006;295:1681-1687

Endogenous Glucose Production After a Mixed Endogenous Glucose Production After a Mixed

Meal in Diabetic and Non-Diabetic IndividualsMeal in Diabetic and Non-Diabetic Individuals (Singhal P et al AJP 2002 )(Singhal P et al AJP 2002 )

Routes of Post-Prandial Routes of Post-Prandial Glucose DisposalGlucose Disposal

Post-Prandial Glucose Post-Prandial Glucose Metabolism : MechanismMetabolism : Mechanism

Study of 11 normal volunteers after a Study of 11 normal volunteers after a standard test mealstandard test meal

Triple isotope technique and indirect Triple isotope technique and indirect calorimetrycalorimetry IntravenousIntravenous

• Tritiated GlucoseTritiated Glucose• C-14-labelled bicarbonateC-14-labelled bicarbonate

OralOral• Deuterated GlucoseDeuterated Glucose

Woerle HJ et al .Am J Physiol Endocrinol Metab 284: E716-E725, 2003

Post-Prandial Glucose Post-Prandial Glucose Disposal Disposal ( Woerle Hans J et al AJP Endo Metab 2003 )( Woerle Hans J et al AJP Endo Metab 2003 )

Changes in Postprandial Glucose Changes in Postprandial Glucose Metabolism in Type 2 DMMetabolism in Type 2 DM

Use triple isotope technique and indirect calorimetryUse triple isotope technique and indirect calorimetry

DM pts had: DM pts had: increased overall glucose releaseincreased overall glucose release Increased gluconeogenesis and glycogenolysisIncreased gluconeogenesis and glycogenolysis ~90% of the increased glucose release occurred ~90% of the increased glucose release occurred

in the first 90 min post-prandialin the first 90 min post-prandial In DM glucose clearance and oxidation were In DM glucose clearance and oxidation were

reducedreduced Non-oxidative glycolysis was increasedNon-oxidative glycolysis was increased Net splanchnic glucose storage was reduced ~ Net splanchnic glucose storage was reduced ~

45% d.t. increased glycogen cycling45% d.t. increased glycogen cycling

Woerle HJ et al Am J Physiol Endocrinol Metab 2006

Effect of Pre- or Post-Meal Exercise on Effect of Pre- or Post-Meal Exercise on

Glycemic ControlGlycemic Control (Yamanouchi K et al Diab Res & Clin (Yamanouchi K et al Diab Res & Clin

Pract, Oct 2002 )Pract, Oct 2002 )

Effects of 2h Post-Prandial Glucose +/- Effects of 2h Post-Prandial Glucose +/-

Vitamins C +E on Flow-Mediated DilatationVitamins C +E on Flow-Mediated Dilatation ( Title ( Title

LM et al JACC Dec 2000 )LM et al JACC Dec 2000 )

Relative risk for death increases with Relative risk for death increases with 2-hour blood glucose irrespective of 2-hour blood glucose irrespective of

the FPG levelthe FPG level

<6.1 6.1–6.9 7.0

11.1

7.8–11.0

<7.8

Fasting plasma glucose (mmol/l) 2-ho

ur p

lasm

a gl

ucos

e

(mm

ol/l)

2.5

2.0

1.5

1.0

0.5

0.0

Haz

ard

rat

io

Adjusted for age, center, sexDECODE Study Group. Lancet 1999;354:617–621

THE FUNAGATA DIABETES STUDY

Impaired Glucose Tolerance is a CV Risk Factor

Tominaga M, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. Diabetes Care1999;22:920-4.

NormalIGT (2 hr PG 140-200)DM (2 hr PG >200)

1.00

Cumulative Cardiovascular Survival

0.99

0.98

0.97

0.96

0.95

0.94

0

1.00

0.98

0.96

0.94

0.92

0

NormalIFG (FPG 110-126)DM (FPG >126)

0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7

Year Year

Effect of Acarbose on CVD in Effect of Acarbose on CVD in Patients with IGT ( STOP-NIDDM)Patients with IGT ( STOP-NIDDM)

( Chiasson J-L et al JAMA July 2003 )( Chiasson J-L et al JAMA July 2003 )

SummarySummary

Postprandial glycemia plays a clinically Postprandial glycemia plays a clinically important role in the complications of important role in the complications of diabetesdiabetes

Postprandial glycemia is a major Postprandial glycemia is a major contributor to overall glycemic control contributor to overall glycemic control ESPECIALLY in moderately-well to well ESPECIALLY in moderately-well to well controlled patientscontrolled patients

So How Can We Assess Post-Prandial So How Can We Assess Post-Prandial Glucose Control Clinically ??Glucose Control Clinically ??

Frequent fingersticksFrequent fingersticks HbA1C HbA1C FructosamineFructosamine Continuous Glucose Continuous Glucose

Monitoring SystemsMonitoring Systems HistoricalHistorical Real-timeReal-time

1,5 Anhydroglucitol1,5 Anhydroglucitol

A New Idea !A New Idea !

1,5 Anhydroglucitol1,5 Anhydroglucitol

History of 1,5AGHistory of 1,5AG 1888 1,5AG was discovered in plant of Polygala Senega.

1973 Presence in human body was reported.

1977 Decrease of plasma 1,5AG concentration with uremia and diabetes mellitus was reported.

1979 Blood 1,5AG was determined in Japan.

After this, research on relationship between diabetes mellitus and 1,5AG has become active.

Blood test measuring 1,5-anhydroglucitol (1,5-AG)

1,5-AG is a monosaccharide (similar to glucose structure)1/40 of glucose concentration – healthy human bloodPrimary Source of 1,5-AG – FoodFurther distributed to skin, muscle, and other tissues/organsReabsorbed very efficiently through kidney (urinary excretion is 1/20 of total amount in body)Large Body Pool of 1,5-AG (6-7 times > Blood)Not metabolized much in the body (metabolic turnaround rate at least 3 days)1,5-AG urinary excretion remarkably increases with hyperglycemia!

The structure of 1,5-anhydroglucitol The structure of 1,5-anhydroglucitol (1,5AG)(1,5AG)

O

OH

OH

HO

HO OH

O

OH

OH

HO

HO

D-glucose 1,5-anhydro-D-glucitol（ (1-deoxyglucose)

Fully Automated Enzymatic Method for 1,5 AG Fully Automated Enzymatic Method for 1,5 AG Assay ( Glycomark ) Assay ( Glycomark ) Fukumura Y et al Clin Chem 1994Fukumura Y et al Clin Chem 1994

HRP=Horseradish peroxidase ; PROD= pyranose oxidase; HTB=3 hydroxyriiodobenzoic acid ; 4AAP= 4 aminoantipyrine

Specificity of AssaySpecificity of Assay

The following don’t interfere in The following don’t interfere in concentrations up to 10 grams/L :concentrations up to 10 grams/L : SorbitolSorbitol MannitolMannitol SucroseSucrose LactoseLactose MaltoseMaltose FructoseFructose

1,5 AG Content of Foodstuffs in 1,5 AG Content of Foodstuffs in Japanese DietJapanese Diet

Yamanouchi T et al Am J Physiol 263: E268-E273. 1992

1,5 Anhydroglucitol Specimen 1,5 Anhydroglucitol Specimen RequirementsRequirements

Oral Supply1,5AG

(5-10mg/day)

Blood stream

TissuesInternal Organs

(500-1000 mg)

Kidney

Urinary excretion (5-10mg/day)

Oral Supply1,5AG

(5-10mg/day)

Blood Stream(1,5-AG

LevelLower)

TissuesInternal Organs

(500-1000 mg)

Kidney

Urinary excretion (INCREASED)

A. Normoglycemia

B. Hyperglycemia

GlucoseBlocks

Reabsorption

Physiology of 1,5-AG

Buse JB et al Diab Tech & Ther 2003. 5(3) : 355-363

1,5 AG Kinetics in Humans1,5 AG Kinetics in Humans

Yamanouchi T et al Am J Physiol 263: E268-E273. 1992

Urinary Excretion of Glucose and Urinary Excretion of Glucose and 1,5 AG Fluctuate in Parallel in Rats1,5 AG Fluctuate in Parallel in Rats

Yamanouchi T et al Am J Physio 1990. 258: E423-E427

But…1,5 AG Does Not Fluctuate with But…1,5 AG Does Not Fluctuate with Variations in Plasma BG in Nephrectomized Variations in Plasma BG in Nephrectomized

RatsRats !! !!

Yamanouchi T et al Am J Physio 1990. 258: E423-E427

Fructose , Mannose and 1,5 AG Share Fructose , Mannose and 1,5 AG Share A Common Transport MechanismA Common Transport Mechanism

Yamanouchi T et al Biochim et Bipophys Acta 1996. 1291: 89-95

Renal Tubular Absorption of Glucose and Renal Tubular Absorption of Glucose and 1,5 AG1,5 AG

Normal

Glucose active transporterFructose, mannoseactive transporter

Glucose

1,5AG

Filtration atglomerulus

Reabsorption atrenal tubule

urine

Renal Tubular Absorption of Glucose and Renal Tubular Absorption of Glucose and 1,5 AG1,5 AG

Hyperglycemia

Glucose active transporterFructose, mannoseactive transporter

Glucose

1,5AG

Filtration atglomerulus

Reabsorption atrenal tubule

urine

Renal Tubular Absorption of Glucose Renal Tubular Absorption of Glucose and 1,5 AGand 1,5 AG

Stickle D and Turk J. Am J Physiol Endocrinol Metab 273: E821-E830, 1997

Linearity of 1,5 AG AssayLinearity of 1,5 AG Assay

Nowatzke W et al Clin Chim Acta 2004

Recovery Time of 1,5 AG in Recovery Time of 1,5 AG in Treated Patients with Type 2 DMTreated Patients with Type 2 DM

Yamanouchi T et al Jpn. J. Clin. Med. 47: 2472-2476, 1989

Histograms of serum 1,5AG concentrations Histograms of serum 1,5AG concentrations in Japanese healthy subjectsin Japanese healthy subjects

10 20 30 40 50

1,5AG (µg/mL)

26.6±7.2

Male (n=332)

0

10

20

30

40

50

Fre

quency 21.5±6.0

Female (n=207)

0

10

20

30

40

50

Fre

quency

10 20 30 40 50

1,5AG (µg/mL)

24.6±7.2

Male and Female (n=539)

010203040506070

Fre

quency

10 20 30 40 50

1,5AG (µg/mL)

Distribution of 1,5 AG Distribution of 1,5 AG in a in a Healthy US Healthy US PopulationPopulation

Nowatzke W et al Clin Chim Acta 2004

The mean 1,5AG levels in healthy The mean 1,5AG levels in healthy subjects during 2 years (n=245)subjects during 2 years (n=245)

0

10

20

30

40

Sep-86 Mar-87 Sep-87 Mar-88

1,5A

G (

μg/m

L)

mean±SD

Diurnal change of plasma glucose and 1,5AGDiurnal change of plasma glucose and 1,5AG

▲―▲: healthy◆―◆:IGTOthers: diabetesB: breakfastL: lunchD: dinner

0

5

10

15

20

25

8 12 16 20 24

time (hour)

1,5A

G (

μg/m

L)0

100

200

300

400

8 12 16 20 24

FPG

(m

g/dL

)↑B ↑L ↑D

Histogram of serum 1,5AG concentrationsHistogram of serum 1,5AG concentrations

0

10

20

30

Fre

qu

en

cy

(%)

Healthy (n=539)24.6±7.2 µg/mL

Diabetes (n=808) 7.3±7.1 µg/mL

0 10 20 30 40 50

Serum 1,5AG (µg/mL)

Serum 1,5AG levels in healthy subjects, Impaired-Serum 1,5AG levels in healthy subjects, Impaired-glucose-tolerance, diabetes mellitus, and various other glucose-tolerance, diabetes mellitus, and various other

disordersdisorders

0

10

20

30

40

1,5

AG

(µ

g/m

L)

Healthysubjects(n=539)

IGT

(n=451)

DM

(n=808)

Non-DM

(n=238)

P<0.001

P<0.001

P<0.001

P<0.001

Yamanouchi T et al Diabetes 1991; 40: 52-57

1,5AG1,5AG IndexIndex1,5AG x UG = 16

30

10

20

0

1,5

AG

x U

G

0 42 6 108 12Plasma 1,5AG (µg/mL)

N =47Log y = -0.97 log x + 2.71R = -0.890 (P < 0.0001)

Pla

sma 1

,5A

G (

µg/ m

L) 14.0

4.0

2.0

0.0

8.0

6.0

12.0

10.0

Urinary glucoses (g/day)

1 10 100

1,5-AG Physiology Implication Because 1,5-AG levels fluctuate according to

glucosuria, the response is much more rapid than glycemic markers based on the glycation process (A1C).

Responds Rapidly and Sensitively to Glycemic Changes

Correlation between glycemic control Correlation between glycemic control markers and past fasting plasma glucose markers and past fasting plasma glucose

(FPG)(FPG)

Distribution of 1,5AG to FPG shows hyperbolic dispersion different from HbA1C and fructosamine. Therefore, Spearman's rank correlation coefficient is used here to make comparison between groups.

Measurement point of FPG

1, 5AG HbA1C Fructosamine

same time1 week ago

2 weeks ago3 weeks ago4 weeks ago

r = -0.88r = -0.84r = -0.80r = -0.71r = -0.58

r = 0.27

r = 0.53

r = 0.81

r = 0.51r = 0.72r = 0.80r = 0.73r = 0.54

2 months ago3 months ago

r = -0.39 r = 0.73r = 0.65

Glycemic control markersGlycemic control markers

1,5AGFructosamine

10 89 7 56 4 3 12 0

HbA1C

Bloodglucose

Weeks before measurement

0

Ren

al e

xcre

tion

of g

luco

se (

g/da

y)

Pl a

sma

gluc

ose

(mg/

dL)

300

200

100

100

300

400

200

21 3 54 6 7 98 10

1211 13

Weeks

Changes in various glycemic control markers in Changes in various glycemic control markers in NIDDM patient with poorly controlled glycemia NIDDM patient with poorly controlled glycemia

after starting insulin treatmentafter starting insulin treatment

HbA

1C (

%)

Pla

sma

1,5A

G (

µg/

mL)

20

10

10

15

5

510

Lente 12u 8 6

Clinical Parameters for 1,5 AGClinical Parameters for 1,5 AG

1,5-AG serum concentrations in normal humans vary 1,5-AG serum concentrations in normal humans vary widely (10-40 ug/ml)widely (10-40 ug/ml)

Little change day to day because of large body pool Little change day to day because of large body pool relative to daily intake and metabolic inertnessrelative to daily intake and metabolic inertness

Few normal subjects show an alteration in 1,5-AG level Few normal subjects show an alteration in 1,5-AG level in the normal range during 2-3 yearsin the normal range during 2-3 years

When hyperglycemia occurs (glucosuria), 1,5-AG When hyperglycemia occurs (glucosuria), 1,5-AG serum levels fall rapidly (1-2 days)serum levels fall rapidly (1-2 days)

Individual variance in renal threshold does not appear to Individual variance in renal threshold does not appear to seriously influence clinical utility of 1,5-AG (glucose seriously influence clinical utility of 1,5-AG (glucose fluctuates more widely than individual renal threshold fluctuates more widely than individual renal threshold variance)variance)

Exception – Gestational DiabetesException – Gestational Diabetes

Post-load glucose measurements in OGTTs correlate well with 1,5-AG in subjects with IGT

R=-0.824 R=0.281

1,5 Anhydroglucitol is a better indicator than A1C of postprandial blood glucose levels in IGT subjects

N = 211

Yamanouchi T et al., Clinical Science 2001

Correlation between 1,5AG and Correlation between 1,5AG and HbAHbA1c1c

Cut-off value

HbA1c (Normal range 4.8-5.8%)

1,5

AG

(µ

g/m

L)

5 6 7 8 9 10 11 12 (%)

15

10

5

10 30 4020 50 60 908070

Weeks

Mea

n p

lasm

a g

luco

se (

mg

/dL

)300

200

100

00

16

12

14

6

10

8

4

2

8

5

6

4

3

0

2

1

1,5A

G

(µg

/mL

)

Hb

A1C

(%

)

7

1,5AG, HbA1C, and mean plasma glucose values 1,5AG, HbA1C, and mean plasma glucose values during a 92-weeks period in a patient with Type 1 DMduring a 92-weeks period in a patient with Type 1 DM

Changes of 1,5AG and HbA1C values during a 13-Changes of 1,5AG and HbA1C values during a 13-months period in a patient with Type 2 DMmonths period in a patient with Type 2 DM

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Month

1,5

AG

(µ

g/m

L)1,5AG

0

1

2

3

4

5

6

7

8

9HbA1C

11

10

12

3

4

5

6

7

8

9

Hb

A1

C(%

)

Improvementstage

Improvementstage

exacerbationstage

Glycemic control in Type 2 DM patients Glycemic control in Type 2 DM patients before and after the study treatmentbefore and after the study treatment

5

6

7

8

9

10

11

12

HbA

1c (

%)

Control

Voglibose

0

2

4

6

8

10

12

14

1,5A

G (

μg/m

L)

0

5

10

15

20

25

30

35

M-v

alue

Before after Before after

Measurement of 1,5AG and HbA1c between October and Measurement of 1,5AG and HbA1c between October and April, around the new year, in 17 patients with Type 2 DMApril, around the new year, in 17 patients with Type 2 DM

7.1

7.3

7.5

7.7

7.9

HbA

1c (%

)

5

6

7

8

9

10

Oct Nov Dec J an Feb Mar Apr

1,5

AG

(μg

/mL)

GlycoMark Evaluates Daily Glycemic Excursions in Moderately-Well Controlled

Patients

HbA1c showed no significant differences among all groups

*Plasma 1,5-AG in diet group significantly higher than OHA and MIT groups (P<0.05)

**Plasma 1,5-AG in CIT significantly lower than diet, OHA, and MIT groups (P<0.05)

N = 76 well-controlled type 2 diabetes patients OHA=oral hypoglycemic agents, CIT=Conventional Insulin Therapy, MIT=Multiple Insulin Injection Therapy

6.9

11.5

Kishimoto et al.Diabetes Care 1995)

Objective: Monitor glycemic control following changes in Objective: Monitor glycemic control following changes in antidiabetic medicationantidiabetic medication

56 type 2 diabetic patients treated with oral hypoglycemic 56 type 2 diabetic patients treated with oral hypoglycemic agents for 4 weeksagents for 4 weeks

After 4 weeks, treatment discontinued in half of patients After 4 weeks, treatment discontinued in half of patients and monitored for 2 more weeksand monitored for 2 more weeks

1,5-AG, Glucose, A1C, and Fructosamine were measured1,5-AG, Glucose, A1C, and Fructosamine were measured

Clinical usefulness of serum 1,5-AG in monitoring glycemic control

Yamanouchi T et al., The Lancet 1996

Serial Changes in A1C in Newly Diagnosed Type 2 Diabetes Patients

Group A – 28 patients who continued treatment for 6 weeks

Group B – 28 patients who discontinued treatment after 4 weeks

No Significant Difference

Yamanouchi T et al.Lancet 1996

Serial Changes in 1,5-AG in Newly Diagnosed Type 2 Diabetes Patients Group A – 28 patients who continued treatment for 6 weeks

Group B – 28 patients who discontinued treatment after 4 weeks

P<0.0001

1,5 Anhydroglucitol detected slight change in glycemia

Yamanouchi T et al.Lancet 1996

Judgment standard of 1,5AG1,5AG (µg/mL) State of glycemic

controlAffected by other diseases

Over 14.0 Normal

10.0-13.9 Excellent Renal glycosuria, oxyhyperglycemiapregnancy (after 30 weeks)

Chronic renal failure (serum creatinineover 3.0mg/dL)

Long term high calorie transfusion through central vein starvation

6.0-9.9 Good Pregnancy (34 weeks approximately)Chronic renal failure (serum creatinine

over 3.0mg/dL)Long term high calorie transfusion

through central vein starvation

2.0-5.9 Fair Chronic renal failure (serum creatinineover 3.0mg/dL)

Characteristics of various glycemic control markers

HbA1C Fructosamine 1,5AG

Best correlated with

Post glycemia Recentglycemia

Present glycemia

Time required for significant change

1 month 1-2 weeks 1-several days

Change Sluggish andapproximate

Sluggish andapproximate

Sharp and analytical

Variance Small Small Large

Most changeable in

Medium~ highhyperglycemia

Medium~ highhyperglycemia

Modest hyperglycemia ~ near-normoglycemia

Purpose for useGrapping roughlyglycemiccontrol state

Monitoringglycemiccontrol inhyperglycemia

Grapping glycemiccontrol statemonitoring strictglycemic control

McGill J et al Diabetes Care 2004

FDA Study – Longitudinal ChangesTime point Time point StatisticStatistic

1,5AG1,5AG

ug/mlug/ml

A1CA1C

%%

FructosamineFructosamine

umol/Lumol/L

GlucoseGlucose

mg/dLmg/dL

BaselineBaseline

MeanMean

1.91.9 9.59.5 410.6410.6 225225

Visit 2 (2 weeks)Visit 2 (2 weeks)

MeanMean

Mean% ChangeMean% Change

3.0*3.0*

57.9%57.9%

9.19.1

-4.2%-4.2%

362.4 *362.4 *

-11.7%-11.7%

187.4*187.4*

-16.7%-16.7%


MeanMean


3.7*3.7*

94.7%94.7%

8.8*8.8*

-7.4%-7.4%

340.0*340.0*

-17.2%-17.2%

181.4*181.4*

-19.4%-19.4%


MeanMean


5.0*5.0*

163.2%163.2%

8.2*8.2*

-13.7%-13.7%

317.5*317.5*

-22.7%-22.7%

172.6*172.6*

-23.3%-23.3%

*p<0.05 vs. baseline McGill J et al Diabetes Care 2004

FDA Study – Longitudinal Changes

McGill J et al Diabetes Care 2004

Assessing the Role of 1,5 AG for Monitoring Post-Prandial

Glycemic Excursions

K Dungan, J. Buse , J Largay, M Kelly, E Button, S Kato, S. Wittlin

University of North CarolinaUniversity of Rochester

Dungan K et al Diabetes Care; June 2006

Study to Evaluate 1,5 AG/Glycemic Excursions as Determined by Continuous Glucose Measurements

Moderately-Controlled Patients (n=34) with A1Cs between 6.5 and 8.0 monitored over 7 days

Comparing 1,5 AG , Fructosamine,and Hemoglobin A1C levels to Glycemic excursions above the renal threshold (> 180 mg/dl)

Glycemic excursions measured by CGMS

Objective: To demonstrate the relationship between serum 1,5-AG (relative to A1C and fructosamine) and the occurrence of postprandial hyperglycemia as reflected by CGMS in suboptimally controlled patients with diabetes


Study Methodology

34 Patients

Type 1: 24 Male: 13 UNC: 20

Type 2: 10 Female: 21 UR: 14

Day 1 2 3 4 5 6 7

CGMS Interval 1 Interval 2

Visit 1

1,5AG, A1c, FA

Visit 2

1,5AG, A1c, FA

Visit 3

1,5AG, A1c, FA24-hr urine glucose

UR: University of Rochester

UNC: University of North Carolina


Postprandial Variables

• AUC-180 – measure of total area above 180 mg/dl for (mg/dl*Day)

• Average Postmeal (Maximum) Glucose (mg/dl) – maximum height of each postmeal glucose excursion for breakfast, lunch, and dinner

• Postprandial Index (PI) – 4 variable combination (max glucose levels for post-breakfast, lunch, dinner and AUC-180 - 7 days)


Correlation AUC-180 vs. Glycemic Assay

AUC-180^ AUC-180^ (mg/dl*Day)(mg/dl*Day)

Avg. Avg. A1C A1C

A1C-End A1C-End Interval* Interval*

Avg. 1,5-Avg. 1,5-AG AG

1,5-AG- 1,5-AG- End IntervalEnd Interval

Avg. FA Avg. FA FA- FA- End End IntervalInterval

Interval 1 & 2 Interval 1 & 2 N=34 N=34

R = 0.36R = 0.36p =0.02p =0.02

R = 0.35R = 0.35p =0.02p =0.02

R = -0.48R = -0.48p = 0.002p = 0.002

R = -0.49R = -0.49p = 0.002p = 0.002

R = 0.33R = 0.33p =0.03p =0.03

R = R = 0.380.38p p =0 .01=0 .01

Interval 1Interval 1N=34N=34

R = 0.23R = 0.23p =0.09p =0.09

R = 0.22R = 0.22p =0.11p =0.11

R = -0.36R = -0.36p =0.02p =0.02

R = -0.37R = -0.37p =0.02p =0.02

R = 0.16R = 0.16p =0.18p =0.18

R = R = 0.120.12p =0.25p =0.25

Interval 2Interval 2N=33N=33

R = 0.35R = 0.35p = 0.02p = 0.02

R = 0.34R = 0.34p =0.03p =0.03

R = -0.42R = -0.42p =0.008p =0.008

R = -0.44R = -0.44p =0.005p =0.005

R = 0.37R = 0.37p = 0.02p = 0.02

R = R = 0.390.39p = p = 0.010.01

^AUC-180=area under the curve for glucose greater than 180mg/dL as determined by CGMS software. *End-interval is visit 2 for interval 1, visit 3 for interval 2 and total (1 & 2).

1,5-AG Correlated Better than A1C or Fructosamine to AUC-180


Avg. Maximum Postmeal Glucose vs. Avg. Glycemic Assay

1,5-AG Correlated Better than A1C or Fructosamine to ALL Postmeal Max Values

Avg. A1C Avg. A1C Avg. 1,5-AG Avg. 1,5-AG Avg. FA Avg. FA

Avg. Postmeal Max (Breakfast) Avg. Postmeal Max (Breakfast) N=20N=20

R = 0.12R = 0.12p = 0.31p = 0.31

R = -0.38R = -0.38p =0.05p =0.05

R = -0.003R = -0.003p =0.494p =0.494

Avg. Postmeal Max (Lunch) Avg. Postmeal Max (Lunch) N=23N=23

R = 0.19R = 0.19p = 0.19p = 0.19

R = -0.22R = -0.22p =0.15p =0.15

R = 0.06R = 0.06p = 0.39p = 0.39

Avg. Postmeal Max (Dinner) Avg. Postmeal Max (Dinner) N=22N=22

R = 0.25R = 0.25p = 0.13p = 0.13

R = -0.54R = -0.54p = 0.004p = 0.004

R = 0.35R = 0.35p = 0.06p = 0.06

Combined Postmeal Max (Breakfast, Combined Postmeal Max (Breakfast, Lunch Dinner)- Multiple RegressionLunch Dinner)- Multiple Regression

N=19N=19

R = 0.25R = 0.25 R = -0.57R = -0.57 R = 0.36R = 0.36


Postprandial Index vs. Average Glycemic Assay

1,5-AG Correlated Better than A1C or Fructosamine to the Postprandial Index

Postprandial Postprandial Index (Multi-Index (Multi-variate-PI) variate-PI) N=19N=19

Avg. A1C Avg. A1C Avg. 1,5-Avg. 1,5-AG AG

Avg. FAAvg. FA

R=0.36R=0.36 R=0.58R=0.58 R=0.36R=0.36

*Postprandial Index is the conglomerate multivariable analysis using AUC-180 and post-meal maximum glucose values as the independent variables.


Postprandial Index vs. A1C/1,5-AG Assay Ratio

A1C/1,5-AG Ratio Correlated Better than A1C or 1,5-AG independently to the Postprandial Index

Combination of 1,5-AG and A1C are more predictive of postprandial hyperglycemia

Postprandial Postprandial Index (Multi-Index (Multi-variate-PI) variate-PI) N=19N=19

Avg. A1C Avg. A1C Avg. 1,5-Avg. 1,5-AG AG

Avg. Avg. A1C/Avg. A1C/Avg. 1,5-AG Ratio1,5-AG Ratio

R=0.36R=0.36 R=0.58R=0.58 R=0.66R=0.66

*Postprandial Index is the conglomerate multivariable analysis using AUC-180 and post-meal maximum glucose values as the independent variables.


Average and Premeal Glucose vs. Glycemic Assay

Fructosamine and A1C correlated better than 1,5-AG to both average glucose and premeal glucose variables

Avg. A1C Avg. A1C Avg. 1,5-AG Avg. 1,5-AG Avg. FAAvg. FA

Average Glucose – Average Glucose – CGMS SensorCGMS SensorN = 34N = 34

R = 0.27R = 0.27p = 0.26p = 0.26

R = -0.15R = -0.15p = 0.23p = 0.23

R = 0.40R = 0.40P = 0.04P = 0.04

Combined Combined PrePremeal meal (Breakfast, Lunch (Breakfast, Lunch Dinner) - Multiple Dinner) - Multiple RegressionRegressionN=19N=19

R = 0.42R = 0.42 R = -0.33R = -0.33 R = 0.45R = 0.45


1,5 AG as Adjunct to A1C to Reflect Postprandial Hyperglycemia

1,5 AG is indicative of differing postmeal glucose levels in moderately controlled patients – despite similar A1C levels!

GlycoMark GlycoMark (1,5-AG) (1,5-AG) Range 0-6Range 0-6N=17N=17

A1C A1C (%) (%)

MeanMean

1,5-AG 1,5-AG (ug/ml) (ug/ml) MeanMean

Total AUC-180 Total AUC-180 Glucose Glucose 11

PostMeal PostMeal Glucose-Max Glucose-Max Mean (mg/dl)Mean (mg/dl)

BreakfastBreakfastN=9N=9


LunchLunchN=10N=10


Dinner Dinner N=9N=9

Higher Higher Postprandial Postprandial VariablesVariables

7.387.38 4.554.55 16.2916.29 259259 224224 198198

GlycoMark GlycoMark (1,5-AG) (1,5-AG) Range 6-18Range 6-18N=16N=16

A1C A1C (%) (%)

MeanMean

1,5-AG 1,5-AG (ug/ml) (ug/ml) MeanMean

Total AUC-180 Total AUC-180 GlucoseGlucose11


Breakfast Breakfast N=11N=11


LunchLunch N=13N=13


Dinner Dinner N=13N=13

Lower Lower Postprandial Postprandial VariablesVariables

7.207.20 9.299.29 10.7510.75 228228 196196 162162


GlycoMark Monitors Postprandial HyperglycemiaGlycoMark Monitors Postprandial Hyperglycemia

Postmeal Glucose (mg/dL)

180

230

0

50

100

150

200

250

Patient Group 1 Patient Group 2

(P<0.05)

GlycoMark 1,5-AG (mg/ml)

8.00

5.58

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00


(P<0.05)

Dungan K et al. Diabetes Care (June 2006)

A1C (%)

7.20 7.38

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00


(No Significant Difference)

Patients were sorted by glycemic excursions as measured by CGMS (AUC-180) and subdivided into two populations – bottom 50th percentile (17 patients) and top 50th percentile (17 patients).

Authors’ Conclusions

•1,5-AG (GlycoMark) assay reflects glycemic excursions, often in the postprandial state, more robustly than other established glycemic assays.

•1,5-AG was reflective of varying postmeal glucose levels, despite similarities in A1Cs.

•In clinical practice, A1C and 1,5-AG may be used sequentially, first employing the A1C assay to identify patients who are moderately controlled and then using the 1,5-AG assay to determine the extent of postprandial glycemic excursions.

0

50

100

150

200

250

300

350

400

2/15 2/16 2/17 2/18 2/19 2/20 2/21 2/22

Time (days)

Glu

co

se (m

g/d

L)

0

50

100

150

200

250

300

350

400

2/8 2/9 2/10 2/11 2/12 2/13 2/14 2/15

Time (days)

Glu

co

se (

mg

/dL

)

52 year old female with type 1 DMA1C 7.43%1,5-AG 12.4mcg/dLPPG max 195 mg/dL

49 year old male with type 2 DMA1C 7.27%1,5-AG 4.5mcg/dLPPG max 235 mg/dL

Representative Patients

UNC/Rochester Study Conclusions

In a subset of moderately controlled patients (A1C 6.5 to 8.0), significant postprandial hyperglycemia was present

1,5-AG reflects postprandial hyperglycemia more robustly than established glycemic assays

At similar A1C levels, there may be variability in postprandial hyperglycemia –which is reflected by 1,5-AG levels!!

UNC/Rochester Study Clinical Possibilities

1,5-AG may be used in combination with A1C for better predictability of postprandial hyperglycemia than either assay alone

A Two-Step Sequential Process Might be Used:

1) Use A1C to identify patients who are moderately controlled (A1C 6.5 to 8.0)

2) Use1,5-AG to determine extent of postprandial hyperglycemia

1,5 AG (ug/ml)1,5 AG (ug/ml)Approximate Mean PostmealApproximate Mean Postmeal

Maximum Blood Glucose (mg/dl)Maximum Blood Glucose (mg/dl)

> 12> 12 < 180< 180

1010 185185

88 190190

66 200200

44 225225

< 2< 2 > 290> 290

1,5-AG and Postmeal Glucose Levels1,5-AG and Postmeal Glucose Levels

1,5 Anhydroglucitol as Comprehensive Adjunct to A1CDiagnostic Algorithm

Managing Short-Term Glucose Control Managing Postprandial Glucose Control (PPG)

1,5 AG 1,5 AG (ug/ml)(ug/ml)

DiabetesDiabetes A1CA1C

> 10> 10 Well-Well-ControlledControlled 4 - 64 - 6

5 – 10*5 – 10* Moderately Moderately ControlledControlled 6 - 86 - 8

2 - 52 - 5 Poor ControlPoor Control 8 - 108 - 10

< 2< 2 Very Poor Very Poor ControlControl > 10> 10

1,5 AG (ug/ml)1,5 AG (ug/ml)

Approximate Mean Approximate Mean PostmealPostmeal

Maximum Blood Glucose Maximum Blood Glucose (mg/dl)(mg/dl)

> 12> 12 < 180< 180

1010 185185

88 190190

66 200200

44 225225

< 2< 2 > 290> 290

Performance of 1,5 Anhydroglucitol Performance of 1,5 Anhydroglucitol in Recent Drug Trialsin Recent Drug Trials

Sitagliptin and 1,5 AnhydroglucitolSitagliptin and 1,5 Anhydroglucitol

Evaluated efficacy and tolerability of Evaluated efficacy and tolerability of sitagliptin in Japanese patients with T2DM sitagliptin in Japanese patients with T2DM over 12 weeksover 12 weeks

Initial A1C levels - 6.5 to 10.0%Initial A1C levels - 6.5 to 10.0%

Randomized to sitagliptin (n=75) or Randomized to sitagliptin (n=75) or placebo (n=76)placebo (n=76)

Stein P et al ADA 2006. Poster 537-PStein P et al ADA 2006. Poster 537-P


Change from Baseline to Study End – Comparison of Mean Values

Placebo Sitagliptin 100mg

1,5-AG (μg/mL) Baseline 4.1 5.3

Week 12 3.8 9.7

A1C (%) Baseline 7.7 7.5

Week 12 8.1 6.9



Change from Baseline to Study End

Placebo Sitagliptin 100mg

Between Group Comparison

LS 95% Cl LS 95% Cl LS Difference

95% Cl

A1C 0.41 (0.26, 0.5) -0.65 (-0.80, 0.50) -1.05* (-1.27, -0.84)

1,5-AG

-0.33 (-1.05, 0.38) 4.45 (3.73, 5,17) 4.78* (3.76, 5.80)

*P value <0.001

Change in Postmeal Glucose Compared to A1C and 1,5-AG % Changes (Baseline to Study End)

Absolute Change in 2 hour

postmeal glucose (mg/dL)

A1C Absolute %

change

1,5-AG Absolute %

change

Sitagliptin 100mg

-69.2 -8.6% 83%

Placebo 11.7 5.2% -7.3%


Miglitol and 1,5 AGMiglitol and 1,5 AGClinical Drug Trial – T. Yamanouchi (University of Teikyo)Clinical Drug Trial – T. Yamanouchi (University of Teikyo)

PlaceboN=84

MiglitolN=158

1,5-AG (μg/mL) Baseline 4.5 4.5

Week 12 4.5 10.0*

A1C (%) Baseline 7.3 7.3

Week 12 7.5 7.0*

Comparison of Mean Values

After 4 weeks, mean 1,5-AG was 9.0 ug/ml (p<0.001) compared to baseline

*p<0.001

PPG more than 180

PPG more than 180

Mean Maximum PPG

PPG more than 180

Mean Maximum PPG

BeforeBreakfast

AfterBreakfast

BeforeLunch

AfterLunch

BeforeDinner

AfterDinner

BeforeBreakfast

AfterBreakfast

BeforeLunch

AfterLunch

BeforeDinner

AfterDinner

BG

BG

Patient 1: Age 75, female, type2 DM

Patient2:Age 73, female, type2 DM

Data from Dr Mori in Japan

Pramlintide and 1,5 AGPramlintide and 1,5 AG

Objective: To assess 1,5-AG as a marker Objective: To assess 1,5-AG as a marker of PPG control in Pramlintide-treated of PPG control in Pramlintide-treated patients with type 1 diabetes (T1DM)patients with type 1 diabetes (T1DM)

Initial A1C levels - 7.2 to 8.0%Initial A1C levels - 7.2 to 8.0% Randomized to Pramlintide (n=18) or Randomized to Pramlintide (n=18) or

placebo (n=19)placebo (n=19) Twenty-nine week studyTwenty-nine week study

Lush C et al .AACE 2007 Meeting (Lush C et al .AACE 2007 Meeting (Poster 296)Poster 296)

Pramlintide and 1,5 AGPramlintide and 1,5 AG

Comparison of Changes in Values from Baseline to Week 29

Placebo (n=19) Pramlintide (n=18) Pramlintide vs. Placebo

2-hr PPG excursions

+6.5 +/-7.6 mg/dL -43.9 +/-10.9 mg/dL

P < 0.001

Body Weight +1.3 +/-0.7 kg -2.0 +/- 1.2 kg P < 0.01

A1C 0.22 +/-0.21 % 0.18 +/-0.31 % NS

1,5-AG ug/mlPercent Change

-0.65 +/-0.41-9 +/- 8 %

+0.96 +/- 0.91 +30 +/-16 %

P<0.05P<0.01


Pramlintide and 1,5 AGPramlintide and 1,5 AGConclusionsConclusions

Pramlintide, as an adjunct treatment for T1DM Pramlintide, as an adjunct treatment for T1DM patients on intensive insulin therapy, led to patients on intensive insulin therapy, led to improved PPG and significant reduction in body improved PPG and significant reduction in body weight.weight.

Despite similar reductions in A1C, the change in Despite similar reductions in A1C, the change in 1,5 AG levels was consistent with improvement 1,5 AG levels was consistent with improvement in PPG control in pramlintide-treated subjects, in PPG control in pramlintide-treated subjects, as measured by SMBG.as measured by SMBG.

1,5-AG, as a complement to A1C, may be a 1,5-AG, as a complement to A1C, may be a useful marker of PPG control.useful marker of PPG control.


Exenatide and 1,5 AnhydroglucitolExenatide and 1,5 Anhydroglucitol

Objective: To assess 1,5-AG as a marker Objective: To assess 1,5-AG as a marker of PPG control in Exenatide-treated of PPG control in Exenatide-treated patients with type 2 diabetes (T2DM)patients with type 2 diabetes (T2DM)

144 Patients144 Patients Initial A1C levels – 8.2 +/-1%Initial A1C levels – 8.2 +/-1% Randomized to Exenatide (5 or 10 ug) or Randomized to Exenatide (5 or 10 ug) or

placeboplacebo Thirty week studyThirty week study

Kendall D , Holcombe J et al ADA & EASD Kendall D , Holcombe J et al ADA & EASD 2007 Annual Meetings2007 Annual Meetings

Exenatide and 1,5 AnhydroglucitolExenatide and 1,5 Anhydroglucitol

Exenatide (5 ug)

Exenatide (10 ug)

1,5-AG

ug/ml

Percent Change

+2.7 +/- 0.6*

45.3 +/-11.9

+2.9 +/-0.6 **

69.4 +/-14.6

A1C % -0.5 +/-0.1 -0.9 +/-0.1 **

Correlations: Changes from baseline1,5-AG vs. HbA1C: r = - 0.74; P <0.00011,5-AG vs. fasting plasma glucose (FPG): r= -0.54; P <0.0001When grouped as HbA1C change tertiles patients with larger HbA1C changes from baseline had larger 1,5-AG changes from baseline.1,5 AG changes were more robust than HbA1C changes

Comparison of Changes in Values from Baseline to Study End

* P < 0.05; ** P < 0.01Kendall D , Holcombe J et al ADA & EASD Kendall D , Holcombe J et al ADA & EASD 2007 Annual Meetings2007 Annual Meetings

SummarySummary 1,5 Anydroglucitol appears to be a more robust indicator of 1,5 Anydroglucitol appears to be a more robust indicator of

glycemic excursions than either HbA1C or Fructosamineglycemic excursions than either HbA1C or Fructosamine It is currently FDA-approved and clinically available; might It is currently FDA-approved and clinically available; might

a home kit be of clinical utility !!??a home kit be of clinical utility !!?? 1,5 AG responds more rapidly and sensitively than either 1,5 AG responds more rapidly and sensitively than either

HbA1C or FructosamineHbA1C or Fructosamine 1,5 AG may be a useful clinical adjunct and indicator for 1,5 AG may be a useful clinical adjunct and indicator for

monitoring moderately well-controlled patients with diabetesmonitoring moderately well-controlled patients with diabetes More clinical trials are necessary and underway to explore More clinical trials are necessary and underway to explore

how effective this tool can be and to define other areas in how effective this tool can be and to define other areas in which it may be limited or most helpful which it may be limited or most helpful

1,5 Anhydroglucitol – Key ReferencesDungan K et al Diabetes Care 2006 29:1214- 1219

McGill, J. et al. Circulating 1,5 Anhydroglucitol Levels in Adult Patients With Diabetes Reflect Longitudinal Changes of Glycemia: A U.S. Trial of the GlycoMark assay Diabetes Care 2004

Buse, J. et al. Serum 1,5-Anhydroglucitol (GlycoMark): A Short-Term Glycemic Marker. Diabetes Technology and Therapeutics 2003; 5:355-363.

Dworacka M. et al. 1.5-Anhdro-D-glucitol: A Novel Marker of Glucose Excursions. International J. of Clinical Practice 2002; Supplement 129:40-44 (Eli Lilly Symposium)

Kishimoto M. et al. 1,5-Anhydroglucitol Evaluates Daily Glycemic Excursions in Well-Controlled NIDDM. Diabetes Care 1995; 18(8):1156-1159.

Matsumoto, K. et al. Effects of Voglibose on Glycemic Excursions, Insulin Secretion, and Insulin Sensitivity in Non-Insulin-Treated NIDDM Patients. Diabetes Care 1998; 21(2):256-260.

Yamanouchi T. et al. Estimation of Plasma Glucose Fluctuation With a Combination Test of HbA1c and 1,5-AG. Metabolism 1992; 8: 862-867.

Yamanouchi T. et al. Clinical usefulness of serum 1,5-anhydroglucitol in maintaining glycaemic control. Lancet 1996;347:1514-1518.

Yamanouchi T. et al. Post-load glucose measurements in oral glucose tolerance tests correlate well with 1,5-AG in subjects with impaired glucose tolerance. Clinical Science 2001;101:227-233.

Many Thanks To:Many Thanks To:

Mary Kelly RN…Who is asked to do it Mary Kelly RN…Who is asked to do it all..and succeeds !!all..and succeeds !!

John BuseJohn Buse Kathleen DunganKathleen Dungan Eric ButtonEric Button Shuhei KatoShuhei Kato

Questions ??Questions ??

1,5 anhydroglucitol and the monitoring of postprandial glucose control steven d wittlin m.d. u of...

Documents

load plasma glucose

glucose clearance

increased glucose release

dcct slide

dentistry slide

c fasting plasma glucose

plasma glucose levels

postprandial plasnma